Cells of the gastrointestinal mucosa arise from stem cells and differentiate along four possible pathways into enterocytes, goblet cells, Paneth cells, or enteric endocrine cells. The signals for this differentiation are largely unknown. Furthermore, there are at least 10 different enteroendocrine lineages that have distinct differentiation pathways. One of the goals described in this application proposes to identify the endocrine progenitor cell that gives rise to the different enteroendocrine cell types. The investigator proposes that this is the PYY cell. A second objective will be to determine the specific transcriptional controls that direct the differentiation of two endocrine cell types (cholecystokinin and secretin) precursor cells. The major part of this work will utilize transgenic mice as a model for examining enteroendocrine cell differentiation. First, to establish that enteroendocrine cells arise from a common progenitor, the investigator will target peptide YY cells in cell ablation studies. The Principal Investigator has preliminary data indicating that pluripotent stem cells give rise to PYY progenitors that then differentiate into other endocrine cells. For these studies, two lines of transgenic mice will be used expressing either herpes simplex virus thymidine kinase (HSVTK) or diphtheria toxin targeted to PYY cells. Each of these models has the potential to ablate PYY cells of the intestine. The second aim of these studies will be to characterize the transcriptional controls that may be responsible for differentiation of CCK cells from secretin cells. This hypothesis has arisen from studies demonstrating that the developmental relationship between CCK and secretin-expressing cells may be similar. The objective of this aim is to identify and characterize cis regulatory domains of the CCK gene that may enhance expression in enteroendocrine cells. The transcription factors that interact with the regulatory elements will be compared between the CCK and secretin genes.